System for monitoring and controlling blood glucose

ABSTRACT

Systems are disclosed which utilize implanted glucose sensitive living cells to monitor blood glucose levels. The implanted cells produce a detectable electrical or optical signal in response to changes in glucose concentration in surrounding tissue. The signal is then detected and interpreted to give a reading indicative of blood glucose levels. Capsules containing glucose sensitive cells and electrodes for detecting electrical activity are also disclosed. Methods of monitoring blood glucose are also described utilizing the systems and capsules disclosed.

FIELD OF THE INVENTION

The present invention relates to means for monitoring the level ofglucose in blood and bodily tissues. Particularly, the invention relatesto a system for monitoring glucose with glucose sensitive cells thatproduce an electrical response to glucose levels in their surroundingmedium which is then used to determine the blood glucose level, toadminister insulin or to take other measures to alter the blood glucoselevel such as diet adjustment.

BACKGROUND OF THE INVENTION

Diabetes is a metabolic disorder that afflicts tens of millions ofpeople in the developed countries of the world, with many millions moreprobably affected in underdeveloped nations. Diabetes results from theinability of the body to properly utilize and metabolize carbohydrates,particularly glucose. Normally, the finely-tuned balance between glucosein the blood and glucose in bodily tissue cells is maintained byinsulin, a hormone produced by the pancreas which controls, among otherthings, the transfer of glucose from blood into body tissue cells.Upsetting this balance causes many complications and pathologiesincluding heart disease, coronary and peripheral artery sclerosis,peripheral neuropathies, retinal damage, cataracts, hypertension andcoma and death from hypoglycemic shock.

In patients with insulin-dependent diabetes, the symptoms of the diseasecan be controlled by administering additional insulin (or other agentsthat have similar effects) by injection or by external or implantableinsulin pumps. The "correct" insulin dosage is a function of the levelof glucose in the blood. Ideally, insulin administration should becontinuously readjusted in response to changes in blood glucose level.However, at present, blood glucose levels can only be determineddirectly by a blood sample. Unfortunately, since drawing the sample isinvasive, blood glucose is usually only determined once daily or lessoften. As a result, insulin dosage is not optimally coordinated withblood glucose levels and complications can continue to be manifested. Itwould, therefore, be desirable to provide non-invasive means for moreclosely monitoring blood glucose levels and coordinating insulin dosageswith such levels.

Many attempts have been made to develop a reliable less invasive ornon-invasive way to measure blood glucose level. One of the most widelyused methods has been measurement of glucose excreted in the urine,which is under certain conditions an indicator of blood glucoseconcentration. In its most convenient form, a "dipstick", which has beencoated with chemical reagents, is dipped into a urine sample. Glucose inthe urine then reacts with the chemical reagents on the dipstick toproduce a color change which corresponds to the appropriate range ofconcentration. The level of urine glucose is then correlated with bloodlevels on the basis of statistical data and previous experience with thespecific patient. However, urine testing has presented severaldrawbacks. Foremost, is the tenuous link between urine glucose level andblood glucose levels. Although general trends in blood levels within acertain range are usually reflected in urine levels, moderate orperiodic fluctuations of blood levels may not be reflected in urinecontent. Therefore, any dosage change made on the basis of urineanalysis is not finely-tuned to blood levels. Furthermore, othersubstances in urine can cause inaccuracy in measurement by interferingwith chemical reactions necessary to produce the color change on thedipstick. Finally, like blood sampling, urine analysis can only beperformed at relatively widely spaced intervals when the patientproduces urine for analysis.

Other systems have been proposed for monitoring blood glucose levels byimplanting a glucose sensitive probe into the patient. Such probes havemeasured various properties of blood or other tissues, including opticalabsorption, electrochemical potential and enzymatic products. U.S. Pat.No(s). 4,436,094 and 4,704,029 disclose two examples of blood glucoselevel probes. U.S. Pat. No. 4,436,094 utilizes an implantable electrodewhich contains a charged carbohydrate species which, in the absence ofglucose, is bound to a component of the electrode and does not affectthe potential measured by the electrode. In the presence of glucose,however, charged carbohydrate is displaced from the binding component bymolecules of glucose, and as a result of its charge, affects thepotential measurement by the electrode. The measured potential can thenbe correlated to the concentration of glucose.

U.S. Pat. No. 4,704,029 discloses an implantable glucose monitor thatutilizes a refractometer which measures the index of refraction of bloodadjacent to an interface with the transparent surface of therefractometer by directing laser light at the interface to measure theindex of refraction of the blood by the amount of radiation reflected atthe interface. As the blood glucose concentration increases, the indexof refraction of blood increases. By comparing the intensity of thelight reflected by the blood with the intensity of light before contactin the blood, glucose concentration can be determined.

Another approach to tying blood glucose levels to insulin dosage hascentered around the implantation of pancreatic cells which produceinsulin in response to changes in blood glucose levels as shown forexample in Altman et al., Diabetes 35:625-633 (1986); Recordi et al.,Diabetes 35:649-653 (1986); Amsterdam et al., J. Cell Biol. 63:1037-1056(1974); Brown et al., Diabetes 25:56-64 (1976); Carrington et al., J.Endocr. 109:193-200 (1986); and Sonerson et al., Diabetes 32:561-567(1983). Altman et al. were able to maintain normal blood glucose levelsin diabetic mice by implanting cells (1) in areas impermeable toantibodies, (2) suppressing the immunogenecity of the implantable cellsin tissue culture before the implantation and (3) enclosing the cells ina capsule that was impermeable to antibodies. However, the implantationmethods of Altman et al. and others are severely limited by theavailability of large enough masses of cells for effective implantationand by the ability to reliably get insulin production over extendedperiods after implantation.

SUMMARY OF THE INVENTION

In accordance with the present invention, systems are disclosed whichutilize implanted glucose sensitive living cells to monitor bloodglucose levels by monitoring glucose levels in body tissues in which theglucose level is in equilibrium with that of the blood. In this respect,the implanted cells are similarly situated to endogenous insulinsecreting glucose sensitive cells. The implanted cells produce adetectable electrical or optical signal in response to changes inglucose concentration in surrounding tissue. The signal is then detectedand interpreted to give a reading indicative of blood glucose levels.This reading can then be used as a basis for altering insulin or otherdrug dosage for injection, as a basis for giving instructions to anexternal implanted insulin pump to alter the amount of insulin deliveredby the pump, or as a basis for taking other corrective measures, such asaltering diet. As a result, blood sugar levels can be more closelymonitored and controlled in a noninvasive way and insulin dosage can bemore closely tailored with concomitant control of symptoms associatedwith diabetes.

A system for monitoring tissue and blood glucose level is disclosedwhich comprises glucose sensitive cells which are capable of producing asignal in response to changes in glucose concentration in the mediumsurrounding the cells. The signal produced can either be electrical oroptical. In certain embodiments, the cells are contained in a capsulewhich is constructed from a membrane or similar substance which isimpermeable to antibodies, yet permeable to nutrients to keep the cellsalive. The capsule can also be fitted with means for collecting thesignals produced by the cells.

In instances where the signal is electrical, these collecting means canbe metal electrodes which are placed in contact with the cells such thatthe signal produced by the cells can be measured as a potentialdifference between the electrodes. The system can further include animplanted signal pickup device which is connected to the electrodes inthe capsule for processing (e.g., amplifying and modulating) the signalfor later transmission through the body surface, such as the skin, orfor transmission to an external or implanted insulin pump. Once thesignal is processed the pickup device passes the signal on to means fortransmitting the processed signal. In other embodiments, the implantedcells produce an electrical signal which can be detected by externalelectrodes without employing electrodes in the capsule or an implantablesignal pick-up device.

In instances where the signal is optical, the signal is produced by achange in the optical qualities of the cells or specifically themembranes of the implanted cells. Preferably, the signal is produced bydyes contained within or coated on cellular membranes which will changethe optical properties of the cells in response to changes in electricalactivity of the cell. This change in optical quality can be detectedthrough relatively transparent body surfaces, such as thin skin layersor fingernails. Alternatively, the optical change can be measured by animplanted optical detector which processes the detected signal much asthe implanted pick-up device previously described processes electricalsignals. The processed signal can be used to control an insulin pump ortransmitted through the skin for external detection.

The electrical signal or the optical signal is detected through the skinby an external sensor and then correlated to a corresponding bloodglucose level. The sensor includes means for detecting the signal, meansfor processing such signal and correlating it to the corresponding bloodglucose level, and output means for reporting or relating the bloodglucose level as determined.

Alternatively, the implanted signal pickup device can pass a processedsignal on to an implanted insulin pump, which, in response to suchsignal, delivers an appropriate dosage of insulin corresponding to thedetermined blood glucose level.

Capsules for use in practicing the present invention are also disclosedwhich comprise a membrane which is impermeable to artibodies and ispermeable to nutrients necessary for cell growth. Glucose sensitivecells are enclosed within the membrane, along with electrodes in contactwith the cells such that changes in the electrical activity of the cellscan be detected as a potential difference between the electrodes.

Alternatively, in place of the electrodes, the capsules can enclosemeans for "shorting-out" the interior of the capsule with respect to theexterior of the capsule such that the electrical activity of the cellsis optimally dissipated on the exterior of the capsule. As a result, theelectrical activity will be maintained at a level which can be detectedby appropriate sensing means.

Capsules are also disclosed which contain glucose sensitive cells whichhave been treated such that the cellular membranes of the cells arecoated with dyes which are sensitive to change in cellular membranepotential.

Finally, methods of monitoring the blood glucose level employing thecapsules and systems of the present invention are disclosed. Basically,those methods comprise implanting into the patient glucose sensitivecells, detecting the signal produced by the cells in response to levelsand/or changes in glucose concentration and correlating that signal withthe corresponding blood glucose level. Methods of administering glucoseare also disclosed which comprise administering a level of insulin (orother correcting agent) appropriate to the blood glucose leveldetermined in accordance with the methods disclosed herein. Such insulincan be either administered manually or by operation of an external orimplanted insulin pump which is connected to the detecting andmonitoring system. It is understood that other therapeutic agents whichwill alter blood glucose levels, such as those sold under the tradenames"Dia Beta" (glyburide; Hoechst-Roussel), "Glucontrol" (qlipizide;Pfizer) and "Diabinese" (chlorpropamide; Pfizer), can be substituted forinsulin as described herein.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1. is a schematic representation of the components and operation ofa system of the present invention.

FIGS. 2A-2F depict bursts of spiked electrical activity produced bypancreatic beta cells in response to various glucose concentrations.

FIGS. 3A-3F contain graphs of electrical activity of six differentpreparations of beta cells in response to varying glucose concentration.

FIGS. 4 and 5 are schematic representations of the electrical componentsof systems of the present invention.

FIGS. 6A, 6B and 7 depict possible arrangements of the components of asystem of the present invention with respect to the skin.

FIG. 8 depicts one embodiment of a system of the present invention thatutilizes an optical signal.

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1 schematically describes one embodiment of a system of the presentinvention which is described in further detail below. As shown at theupper right of FIG. 1, glucose diffuses from the bloodstream into theextracellular space in bodily tissues. Eventually the glucose diffusesto implanted glucose sensitive cells which are a part of the system ofthe present invention. The implanted cells respond by exhibitingelectrical activity, such as a change in membrane potential,commensurate with the concentration of glucose in the extracellularspace.

The electrical activity can be detected or monitored in one of two ways.Where the electrical activity is strong enough to be detected through abody surface (e.g., layers of skin), the electrical activity is detecteddirectly by an external signal sensor. Alternatively, the electricalactivity is monitored by an implanted signal pickup device. The pickupdevice processes and amplifies the electrical activity. The amplifiedsignal is then transmitted through a body surface (such as the skin) andis detected by the external signal sensor.

The external signal sensor contains or is connected to a decoder ormicroprocessor that interprets the signal. The decoder correlates thesignal with blood glucose concentration on the basis of an algorithm andprogrammed information relating to the correlation between blood glucoselevels and glucose levels at the implantation site for the patient inwhich the system is implanted. For example, the microprocessor can beprogrammed to correlate a glucose concentration of 20 MM at theimplantation site with a concentration of 22 MM in the blood on thebasis of prior and periodic blood sampling. Once the signal has beencorrelated and translated into a reading of the blood glucoseconcentration, the concentration information is used in one of two ways.First, the information can be displayed for reading by the patient or aperson caring for the patient. On the basis of the displayedconcentration, the correct insulin dose can be administered or diet canbe adjusted. Alternatively, the concentration information is fed into aninsulin pump, external or implanted, that infuses the correct insulindosage on the basis of the determined blood glucose level. Theconcentration information can also be fed to other devices (such asautomatic liquid feeding apparatus) which will take corrective action onthe basis of such information.

The systems of the present invention utilize glucose sensitive livingcells as sensors of the blood sugar levels either directly (byimplantation in the bloodstream) or indirectly (by implantation intissues in equilibrium with blood glucose levels). Any cell type thatproduces a detectable electrical activity in response to changes inglucose concentration in the surrounding environment can be used inpracticing the present invention.

Beta cells from the islets of Langerhans in the pancreas are preferredglucose sensitive cells. Beta cells have been shown to produceelectrical activity, action potentials, in response to glucoseconcentration and have the advantage that they respond properly toglucose in the concentration range relevant to patient monitoring. Scottet al., Diabetologia 21:470-475(1981); Pressel et al., Biophys. J.55:540a (1989); Hidalgo et al., Biophys. J. 55:436a (1989); Atwater etal., Biophys. J. 55:7a (1980). Beta cells respond to glucose in burstsof spikes of electrical activity. The spike frequency, burst durationand pauses between bursts are all functions of glucose concentration.FIGS. 2 and 3 present data relating to the electrical activity of betacells. As shown in FIG. 2, the burst duration increases as glucoseconcentration increases. The pause between bursts also decreases asglucose concentration increases. In FIG. 3, the spike frequency(spikes/second) increases as glucose concentration increases. Each ofthese parameters (burst duration, pause duration and spike frequency),as well as spike shape, can be monitored alone or in combination as asource of signal corresponding to cellular electrical activity. It hasalso been established that the beta cells are electrically coupled,resulting in synchronized electrical activity of the cells. Eddlestoneet al., J. Membrane Biol. 77:1-141 (1984), Meda et al., Quarterly J.Exper Physiol. 69:719-735 (1984). Therefore, in response to a change inthe glucose concentration, many cells fire their action potentials orelectric signals in synchrony, producing a significantly amplifiedsignal which is easier to detect.

Methods for isolating beta cells are described in the references citedin the preceding paragraph and in Amsterdam et al., J. Cell Biol.63:1037-1056 (1979); Ricordi et al., Diabetes 35:649-653 (1986); andCarrington et al., J. Endocr. 109:193-200 (1986). In addition, any othermethod for isolating beta cells can be used which preserves the abilityof the isolated cells to respond to changes in glucose concentration.Other methods for culturing pancreatic cells are disclosed in Amsterdamet al, J. Cell Biol. 63: 1037-1073 (1974); Amsterdam et al., Proc. Natl.Acad. Sci. USA 69:3028-3032 (1972); Ciba Foundation Symposium on theEndocrine Pancreas, Reuck and Cameron, ed., p. 23-49 (J. and A.Churchill Ltd., London 1962); and Howard et al., J. Cell Biol.35:675-684 (1967).

Sensor cells in taste buds have also been shown to respond tofluctuations in glucose concentration. Ozeki, J. Gen. Plysiol.58:688-699 (1971); Avenet et al., J. Membrane Biol. 97:223-240 (1987);Tonosaki et al.; Brain Research 445:363-366 (1988). Taste cells showparticular advantage for systems of the present invention because undersuitable conditions such cells regenerate every few days by continuousdivision. Thus, prolonged growth of these cells when implanted is morereadily sustained. Taste cells are also more accessible than beta cells.A sample of taste cells can be removed from a patient with only minorsurgery, grown in culture to obtain a sufficient number of cells andthen implanted. The ability to use a patient's own cells also reducedthe likelihood of immunologic reactions to the implant. Taste cells canbe isolated according to the methods of the publications cited above orby any other method which preserves the ability of the cells to respondto change in glucose concentration.

Alpha cells from the pancreas have also been shown to be sensitive toglucose concentration in the surrounding medium. Sonerson et al.,Diabetes 32:561-567 (1983). Transformed cell lines, such as the insulinproducing line disclosed in U.S. Pat. No. 4,332,893, and hydridoma linescan also be used. Any electrical activity associated with the responseby alpha cells or transformed lines to glucose can be harnessed inpracticing the present invention.

Many methods are known for implanting beta cells in human tissues.Altman et al., Diabetes 35:625-633 (1986); Ricordi et al., Diabetes35:649-653 (1986); Brown et al., Diabetes 25:56-64 (1976); Schmidt etal., Diabetes 32:532-540 (1983). Other means for encapsulating livingcells are disclosed in U.S. Pat. No(s). 4,663,286, 4,409,331, 4,352,883,4,798,786, 4,689,293 and 4,353,888. Although the implanted cells of thepresent invention need not necessarily be encapsulated, any of thesemethods can be employed to produce an implantable capsule where such isused. The method of Altman et al. is preferred. The Altman capsule is athin walled (about 100 microns thick) tube or elongated pellet made of apolyvinyl chloride acrylic copolymer, with a diameter of about 1 mm.These dimensions are preferred to maintain proper diffusion to allcells. The molecular-weight cut off of the Altman et al. capsulemembrane was approximately 50,000. In preferred embodiments of thepresent invention, the cut off is less than 50,000 and most preferablybetween 1,000 and 10,000.

The capsule serves two basic functions. First, it serves as a barrierthat prevents the cells from migrating away, while nutrients and wasteproducts are free to diffuse through the capsule. Second, it serves toprevent antibodies and other large molecules from leaving or enteringthe capsule, for example, to prevent immunological reactions. Thecapsule also allows the use of glucose sensitive tumor cell lines assensor cells which must be contained to prevent proliferation. Anymaterial which will provide these functions can be used to form capsulescontaining glucose sensitive cells.

In some embodiments, while not significantly interfering with productionand detection of cellular electrical activity, the capsules are equippedwith means for aiding detection of cellular electrical activity, such aselectrodes or conducting bars that short-circuit the cell electricactivity with the outside. The capsules are also preferably implanted inclusters sc as to ensure a detectable signal even if one or morecapsules becomes dysfunctional. The capsules may also contain means tofix them in the desired location or materials useful for determining thelocation of the capsules, such as radio-opaque materials.

Where the electrical activity is too low to be detected through the bodysurface without amplification or where the electrical activity is to beharnessed to drive an insulin pump, electrodes are placed on the insideof the capsule such that a potential difference can be measured acrossthe electrodes which corresponds to the electrical activity of the cellsinside the capsule. To prevent cell damage, these should be made from aninert metal, such as those commonly used in a variety of implants. Seefor example, "Cardiac Pacing and Physiology," Proceedings of the VIIIthWorld Symposium on Cardiac Pacing and Electrophysiology, Jerusalem,Israel, June 2-11, 1987, ed. Belhassen et al., (Keterpress Enterprises,Jerusalem); IEE Trans. Biomed. Eng. 34:664-668 (1987); and J. Am. Coll.Cardiol. 11: 365-370 (1988). Since these electrodes are used for signalpickup only and not for electric stimulation, their functional lifetimeshould be practically indefinite. The electrodes are connected byinsulated wires to an implanted signal pickup device for processing andamplification or to the insulin pump.

First, where the electrical activity of the implanted cells generateselectric signals strong enough to be picked up from the external bodysurface by electrodes (as in EEG or ECG), the capsules are implantednear the surface of the skin where the skin is very thin and thelocation convenient. As shown in FIG. 6B, the signal is then detected bythe external signal sensor. Alteratively, where the electrical activityis too small to be picked up by external means, electrodes areintroduced into the capsule and connected to the implanted signal pickupdevice as shown in FIG. 6A. In this case the capsule implantation can bedone anywhere in the body, for example, the peritoneal cavity whereimplantation is relatively easy and vascularization is adequate.

The basic components of the implanted signal pickup device are shown inFIG. 5. Basically, the device resembles implanted pacemakers in itsexternal surface property. It can contain some or all of the followingelements as necessary to provide a processed signal which is suitablefor transmission or other desired use:

1. Inputs connected to the electrodes inside the implanted capsules.

2. A number of low noise, high input impedence differentialpreamplifiers corresponding to the number of capsules. Preferably, eachcapsule is connected to a single differential input amplifier.

3. Band pass filters at the outputs of the amplifiers. In certainembodiments, each amplifier may be connected through two filters, onedesigned to pass only the spikes (action potentials) while the otherwill pass only the very slow potential shifts associated with each burstof activity.

4. An integrating amplifier or microprocessor that sums up the output ofall the preamplifiers.

5. A coding and modulating microprocessor that processes the summedsignal so as to be best suitable for transmission across the skin, suchas FM modulation.

6. A power amplifier that boosts the processed signal and is connectedto the transmitter that sends the processed signal through the skin.

There are two preferred alternative modes of transmission of the datafrom the internal implanted amplifier across the skin to the externalsensor. In the first alternative, the amplifier is driven by lowamplitude local currents by means of a pair of electrodes implantedunder the skin. The electric field thus created is similar to thosegenerated by the heart (such as in ECG measurement) and can be detectedsimilarly by external electrodes. AC modulation of these currents willprevent local tissue stimulation, electrode polarization, and the like.In the second alternative, the output of the amplifier is fed, afterproper modulation, to an induction coil or a coupling capacitive signaltransferer. This coil generates an electromagnetic field that is pickedup by a similar externally positioned coil. Other means for transmittinga signal across the tissue barrier will be apparent to skilled artisansand may be used in practicing the present invention.

The signal from the capsules or the transmitter of the signal pickupdevice is detected by an external signal sensor. The basic components ofthe signal sensor are shown in FIGS. 4 and 6. In certain embodiments,the signal sensor can include one or more of the following elements:

1. A sensor, such as an electrode, coil or other means suited to detectthe electrical or optical signal transmitted through the body surface.

2. A preamplifier connected to the sensors (which may not be necessarywhere the signal is already amplified before transmission across theskin barrier).

3. A filter for external noise reduction.

4. A demodulator--decoding microprocessor that separates the signalsfrom their FM carrier or other modulation means when such a mode oftransmission is used.

5. A signal processor that utilizes the appropriate algorithms andprogrammed information relating to glucose concentration to translatethe transmitted signal into the corresponding glucose concentration.

The processed and decoded signal corresponding to determined glucoseconcentration is then passed on to means for outputting such informationin the desired manner. For example, the concentration information can bepresented as a digital readout in the form of a digital display on theprobe itself or a display and printout in an associated device. A memorymay be used to save the glucose values obtained during continuous orfrequent glucose level monitoring. Such information including integratedglucose levels may also be used for determination of the correct amountsof insulin or insulin like drugs to be taken by the patient ordetermining patient diet. Such information can be displayed for patientuse or as an input to an automated insulin infusion device.

A calibration system can also be associated with the system of thepresent invention. Since the exact dependency of electrical activity ofthe implanted cells on glucose concentration may vary with time, a meansfor recalibration of the system is provided. Upon calibration theexternal device or probe is put into calibration mode. The current bloodglucose level, as determined by a blood sample or other reliable meansis PG,24 fed manually (or automatically) to the calibration circuit thatwill reset the proper parameters of the concentration determiningalgorithms. A second glucose determination may be necessary at times toobtain two points on the calibration curve. Calibrations can beperformed as frequently or infrequently as necessary to achieve andmaintain the desired degree of accuracy in glucose level determination.

As shown in FIG. 7, in certain embodiments the processed signal is usedto control an implanted insulin pump. By means of the controller thepump output is kept relatively consistent with the blood glucose levelsthus allowing the pump to more closely mimic the human pancreas. Mostcommercially available implantable pumps can be adapted for such usegiving the pump similar properties to those of the beta cells.

An alternate embodiment of a system of the present invention convertsthe electrical activity of the glucose sensitive cells into an opticalsignal. Direct changes in cell optical properties resulting fromelectrical activity can be measured as an optical signal. Alternatively,biocompatible dyes which are sensitive to electric fields can beincorporated into the cell membranes and subjected to the membranepotential or electric field. Dyes useful for practicing this embodimentare disclosed in Grinvald et al., Physiol. Rev. 68:1285-1366 (1988) andGross et al., Biophys. J. 50:339-348 (1986). Other suitable dyes includethose commercially available from Molecular Probes, Inc., Eugene,Oregon. The changes in the membrane potential induce changes in theoptical properties of untreated cells or dyed cells, for example, in theoptic density, fluorescence or birefringence of the cell membranes.Thus, the action potentials or electric spikes that the cells generatein response to glucose concentration induce changes in the opticalproperties of the cells (i.e., they generate optical signals). Thesesignals are picked up by an implanted or external optic sensor. Incertain embodiments, the cells are implanted such that a transparentbody surface, such as thin skin layers or fingernails, separates themfrom the outside world. In optical signal embodiments, if a capsule isused, it must be constructed from a material through which the opticalchanges can be stimulated and measured (e.g., practically all thinplastics). One such implantation of cells is shown in FIG. 8. As shown,an external optical sensor monitors the cell activity and translates itinto glucose concentration data. The external sensor can include a lightsource of the proper wavelength to excite the dyes or to be reflectedfrom the cell surfaces and other components previously described for theexternal electrical signal sensor for processing, decoding andoutputting the signal. Alternatively, the optical sensing components canbe implanted such that an electrical signal, corresponding to theoptical signal, is produced which can be detected or transmitted throughthe skin.

All of the literature and patent references identified herein areintended to be incorporated within the disclosure.

We claim:
 1. A system for monitoring glucose levels in a patient's bodytissues, said system comprising:implantable glucose sensitive livinganimal cells capable of producing an electrical or optical signal inresponse to the glucose concentration in the medium surrounding saidcells in the patient; and means for detecting said electrical or opticalsignal.
 2. The system of claim 1 wherein said signal is an electricalsignal.
 3. The system of claim 2 wherein said cells are contained in acapsule and wherein the means for detecting said electrical or opticalsignal comprises collecting means in said capsule for collecting saidelectrical signal from said cells.
 4. The system of claim 3 wherein saidcollecting means are metal electrodes in contact with said cells suchthat said signal can be measured as a potential difference between saidelectrodes.
 5. The system of claim 4 wherein the means for detectingsaid electrical signal further comprises an implantable signal pickupdevice connected to said electrodes for processing said signal fortransmission.
 6. The system of claim 5 wherein the means for detectingsaid electrical signal further comprises transmission means connected tosaid pickup device for transmitting said processed signal through a bodysurface.
 7. The system of claim 1 wherein said signal is optical.
 8. Thesystem of claim 7 wherein said signal results from changes in theoptical qualities of said cells.
 9. The system of claim 8 wherein saidoptical qualities are changed by dyes in or on the membranes of saidcells that are affected by changes in the membrane potential of saidmembranes.
 10. The system of claim 8 wherein the means for detectingsaid optical signal comprises an implantable optical sensing devicepositioned with respect to said cells so as to detect and process saidsignal for transmission.
 11. The system of claim 10 wherein the meansfor detecting said optical signal further comprises transmission meansconnected to said implantable optical sensing device for transmittingsaid processed signal through a body surface.
 12. The system of claims6, 7 or 11 wherein the means for detecting said electrical or opticalsignal comprises sensor means for detecting said transmitted signalthrough said body surface and for correlating said transmitted signal tosaid glucose concentration.
 13. The system of claim 12 wherein saidsensor means comprises:detector means for detecting said transmittedsignal; processor means connected to said detector means for correlatingsaid transmitted signal to said glucose concentration; and output meansconnected to said processor means for reporting said glucoseconcentration.
 14. The system of claim 5 further comprising an insulinpump connected to said pickup device such that said pump delivers adosage of insulin appropriate to said glucose concentration.
 15. Thesystem of claim 10 further comprising an insulin pump connected to theimplantable optical sensing device of the means for detecting saidelectrical or optical signal, such that said pump delivers a dosage ofinsulin appropriate to said glucose concentration.
 16. The system ofclaim 1 wherein said cells are selected from the group comprising betacells, alpha cells and taste cells.
 17. The system of claim 16 whereinsaid cells are beta cells.
 18. A method of monitoring the glucose levelof a patient, said method comprising:implanting into said patientglucose sensitive living animal cells capable of producing an electricalor optical signal in response to glucose concentration in the mediumsurrounding said cells in the patient; detecting said signal; andcorrelating said signal with said glucose concentration.
 19. The methodof claim 18 wherein said signal is detected through a body surface by anexternal signal sensor.
 20. The method of claim 19 wherein said signalis processed by said sensor and correlated with said correspondingglucose concentration.
 21. The method of claim 18 wherein the electricalor optical signal is detected by an implantable signal pickup devicethat processes said signal for transmission through a body surface. 22.The method of claim 21 wherein said processed signal is transmittedthrough said body surface and is sensed externally thereof externalsignal sensor.
 23. The method of claim 22 wherein said transmittedsignal is a sensor correlated with said corresponding glucoseconcentration.
 24. A method of administering a dosage of insulin, saidmethod comprising:implanting into said patient glucose sensitive livinganimal cells capable of producing a signal in response to glucoseconcentration in the medium surrounding said cells; detecting saidsignal; correlating said signal with said glucose concentration; andadministering said dosage of insulin at a level appropriate to saidglucose concentration.
 25. The method of claim 24 wherein said dosage isadministered by an implanted insulin pump.